Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of ... Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011). Patients with FANCB mutations often present with multiple additional congenital anomalies, including the constellation of features designated VACTERL-H, for vertebral defects, anal atresia, tracheoesophageal fistula, esophageal atresia, radial or renal dysplasia, and hydrocephalus. Many patients with these features die in early infancy before developing anemia (McCauley et al., 2011). For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.
The existence of at least 2 separate loci, homozygosity at either of which can result in the Fanconi syndrome, was indicated by the complementation observed by Zakrzewski and Sperling (1980) in cell hybrid studies. They found no complementation ... The existence of at least 2 separate loci, homozygosity at either of which can result in the Fanconi syndrome, was indicated by the complementation observed by Zakrzewski and Sperling (1980) in cell hybrid studies. They found no complementation between cells of classic Fanconi syndrome and those from patients lacking skeletal malformation. However, cells from a late-onset case complemented cells from an early-onset case. Sensitivity to the cytogenetic effects of mitomycin C was the phenotype of which complementation was studied. From comparable complementation studies, Duckworth-Rysiecki et al. (1985) likewise concluded that there are at least 2 complementation groups. Digweed et al. (1988) showed that the complementation grouping established by fibroblast fusion studies correlates with the rate of semiconservative DNA synthesis after 8-methoxypsoralen/UVA-irradiation treatment (Moustacchi et al., 1987). Because of the general nature of the disorder, FA appears to be a prime candidate for somatic cell gene therapy. Diatloff-Zito et al. (1990) reported studies in which transfectants were obtained by mouse DNA-mediated gene transfer into FA primary fibroblasts. These studies again demonstrated differences between complementation groups A and B. Cells from group A, which are the most sensitive to the effects of crosslinking agents, were partially corrected for both the chromosomal aberrations and the cytotoxicity to 8-methoxypsoralen photoaddition. In contrast, after treatment with mitomycin C, only the chromosomal sensitivity was reestablished to a near-normal level. The opposite was true for group B cells, i.e., cell survival to MMC was partially corrected, whereas the frequency of MMC-induced chromosomal aberrations remained close to that of the untransfected cells. Wang et al. (1993) reported a pedigree in which 4 affected males in 3 sibships connected through possible carrier females in 2 generations of a family presented with a VACTERL phenotype with hydrocephalus. This family had previously been reported by Hunter and MacMurray (1987), Evans et al. (1989), and Sommer et al. (1989). Wang et al. (1993) found that affected members of this family had spontaneous chromosome breakage and rearrangements, suggesting that some cases of VACTERL-H hydrocephalus represent severe Fanconi anemia. McCauley et al. (2011) reported 4 unrelated males with variable manifestations of VACTERL-H associated with mutations in the FANCB gene. Two of the affected pregnancies were terminated at 20 weeks' gestation, 1 proband died at age 15 weeks, and 1 died at age 2 years, 10 months. All presented in utero or at birth with multiple variable congenital anomalies including intrauterine growth retardation, dysmorphic ears, vertebral anomalies, esophageal, duodenal, or anal atresia, ventriculomegaly, renal agenesis, and radial agenesis. Two had cardiac defects, 2 had tracheoesophageal fistula, and 2 had small genitalia. Only the patient who lived beyond infancy developed anemia. Three patients studied had evidence of chromosome breakage. Two of the patients had male family members with a similar phenotype, both of whom died within the first month of life. One of the patients belonged to the family previously reported by Hunter and MacMurray (1987) and Wang et al. (1993) as having X-linked VACTERL-H.
In individuals with Fanconi anemia of complementation group B, Meetei et al. (2004) found mutations in the FANCB gene, which they designated FAAP95 (300515.0001-300515.0004). They transfected lymphoblasts from individuals with FA with cDNA encoding FAAP95 and demonstrated that ... In individuals with Fanconi anemia of complementation group B, Meetei et al. (2004) found mutations in the FANCB gene, which they designated FAAP95 (300515.0001-300515.0004). They transfected lymphoblasts from individuals with FA with cDNA encoding FAAP95 and demonstrated that hypersensitivity to mitomycin C (MMC) and monoubiquitination of FANCD2 (227646) were both restored to normal. These data proved that FAAP95 is the gene associated with Fanconi anemia complementation group B. Meetei et al. (2004) suggested that evidence that the BRCA2 gene (600185) underlies complementation group B, as suggested by the work of Howlett et al. (2002), was inconclusive. No complementation of a FANCB cell line by BRCA2 was reported, and no BRCA2 mutation was detected in another FANCB cell line; furthermore, cells with defective or depleted BRCA2 show normal monoubiquitination of FANCD2, unlike FANCB cells, which show defective FANCD2 monoubiquitination. Holden et al. (2006) studied a family in which 2 male fetuses related to each other as nephew and maternal uncle presented with the VACTERL-H phenotype (314390). A fibroblast culture established from the proband fetus showed an increased number of chromosome breaks within the affected range observed in Fanconi anemia cells on breakage studies with diepoxybutane. X-inactivation studies in the mother and maternal grandmother of the proband fetus showed 100% skewing of X inactivation, a feature consistently found in females heterozygous for FANCB mutations. On screening of the 8 coding exons of FANCB, Holden et al. (2006) identified a splice site mutation (300515.0005). Sequencing of both obligate carrier females, mother and maternal grandmother, confirmed that they were heterozygous for the mutation. McCauley et al. (2011) found that 4 of 10 probands presenting with a VACTERL-H phenotype had mutations in the FANCB gene (see, e.g., 300515.0006 and 300515.0007). All patients were male, and all unaffected mothers had skewed X inactivation in peripheral blood.